Fluorosulfonylphenylamido-1, 3-propanediol compositions and process



Patented June 1, 1954 Fi'JUGROSULFONYLPHENYLAMIDO 1a- PROPANEDIOL COMPOSITIONS AND PROCESS Walter A. Gregory, Wilmington, Del., assignor to E. I clu Pont de Nemours and Company, Wil"- mington, Del., a corporation of Delaware N Drawing Application J 111$ 2 1952, Serial No. 296,960

7 claima- (Cl. 260-543) 1 This invention relates to=fluorosulfonylphenylamido-l,.3-propanediolsand to their preparation.

The fiuorosulfonylphenylphenylamido 1,3-

propanediols of the invention :are' representedi-by the formula 1. R" O OH NH -Acyl r g Julia-onion 1 (p-fluorosulfonylphenyl') -2'-italpha,aiphadichloroacetamido)z--Lii propanediol',

1 (p-fiuorosulfonylphenyl'l -2-(a1plfa ,alpha=di bromacetamidol-1,3-propanedioh 1 (4 fluorosulfonyl -2 methylphenylfi '2 (alpha,alpha dichloroacetamidm- -L3 ro:

panediol,

alpha-dichloroacetamido) -1,3 -propanediol; 1 (p fiuorosulfonylphenyl)-2-(alpha-chloro acetamido)-1,3-propanediol,

1 p-fiuorosulfonylphenyl) 2 (alpha bromo-- acetamido) -1,3-propa-nediol,

l (p fiuorosulfonylphenyl):-2-acetami}do-1,3

propanediol,

alpha-dichloroacetamidol1,3=propanediol;

alpha-dichloroacetamido)-l;3prepanediol;

1 (4 fluorosulfonyl-3-ethylphenyl )-2 (alphaalpha-dichloroacetamido) -l ,3-propanediol,

1 (4 fluoro'sulfonyl 2 methoxyphenyD-Z- (alpha,alpha.- dichloroacetamidol 133 propanediol.

The compounds of the inventioncan 'bepr'e V 1 (3-chloro-4-fluorosulfonylphenyl) -2- (ail-gihag- '45 pared from previously: known-'organic compounds by novel syntheses WhichIIshavexdiscovered' In these syntheses there are;:invo'lved a number of new intermediate organic compoundsi andall of the compounds represented-by Formula 1* may exist in optical isomeric form. Stereoisomeric-fornis as used herein refer to the spatial arrangement of the polar groups on the two asymmetric carbon atoms with reference to erythrose and threose. Todifferentiate between these two possible forms the diastereoisomeric pair related to erythrose in configuration will hereinafter be designated as the erythro series and the diastereoisomeric pair related'tothreose as the threo series or form.

To further designate the threo form of the compounds of my invention I have designated as the threo form the major product obtained from the aluminum isopropoxide, isoprop yl-alcohol reduction of the'keton'es ofthe formula O p o NH-Aeyl rs JLcH-omoH where R and acyl have the same significance as in Formula 1.=

Both the threo and erythroform's exist as racemates of optically active dextro (d) and levo Z) rotatory isomers aswell- -a.'sifi"the form of the individual or separated dextro (d) and levo (1) optical isomers.

In View of thedifficulty of representing the various optical" isomerswi-t'h plane'formulas, I have used the customary structural formulas and adapted'the following convention in order to" designate-their optical configuration, an appropriate notation is used under-the formula, for example, (l-thf'eo fornii; (di -threo form, (1)- -erythro form-I -(d-)-eryth'ro form, (dim-threo form and the like.

It will-be under'stoo'di-that 'wh'e'remo notaticiri appears with a structure-1 formu'la i'or with 'a chemical name the formula or name is to be interpreted in its generic sense; that is, as repre senting the (d) -threo, (D 'tlireo isomers or (d)- erythro, (l) -erythio isomers in 'sep'arated form as Certain of -these new "intermediate compounds 'fiuomsul'fonylpiienylamidopropanediols of the follows:

O r- 60111-011. or 01- O \M 8&0 K H o g a a a Step 1 (a) R O F-S JGH:

0 Step 2 lHalogenatlon R o f F-S -b-CHa-X 0 Step 3 lflexemethylenetetramine CH3N R g o O /C 2 F-S -CH: NCH2N CH: 0 3

CH: N X- Step 4 R.

0 t F-(S) CH2NHCH:OSO2H Step 6 1H0! O O t F% CH:NH:HC1

Step 6 lAeylation O F g p OH NH Acyl Step7 weakbaselHCHO O NH-Acyl 0 1] I F% CHCH|OH Meerwein-Ponndorf-Verly Step 8 reduction or NaH B reduction OH NH-Acyl 0 e I F-S H-CH-CHaOH Step 1 of my general process involves preparing a compound of the formula 4 material is a substituted benzenesulfonyl fluoride of the formula The fluoride is mixed with potassium permanganate and magnesium nitrate hexahydrate to yield the desired substituted acetophenone. It i preferred to add an acetone solution of the fluoride to an aqueous system containing the magnesium nitrate and potassium permanganate.

An alternativ route of preparing the substituted acetophenone of Formula 3 involves reacting potassium fluoride in aqueous medium with a compound of the formula R o C1-C8) 8-4113:

The product of Step 1 (Formula 3) is halogenated in Step 2 to give a phenacyl halide of the formula Halogenation can be carried out in a variety of ways. A preferred method is to add bromine slowly to a glacial acetic acid solution of the substituted acetophenone of Formula 3.

In the third step of my process, the phenacyl halide of Step 2 is mixed in a liquid medium such as, for instance, anisole, with hexamethylenetetramine to yield a hexamethylenetetraminium halide of formula GH2N In most instances I have found it preferable to proceed directly to the sulfite of Step 4 without isolation of the hexamethylenetetraminium halide. This conversion is efiected using sulfur dioxide and water. It is shown on the process diagram as Step 4.

The substituted benzenesulfonyl fluoride sulfite resulting from Step 4 can be readily converted into the corresponding hydrochloride using hydrochloric acid (Step 5).

Step 6 comprises N-acylating the amine hydrochloride compound of Step 5. This step is preferably carried out using dichloroacetyl chloride but similar acid halides or acetic anhydride in the presence of a weak base, for instance, sodium acetate, may be used.

The amide derivative produced in accordance with Step 6 of my process is then subjected to an aldol type of condensation to yield a compound having the formula This condensation is preferably carried out in an alcoholic medium, for example, ethanol or methanol, using potassium carbonate or sodium bicarbonate and an aqueous formaldehyde of 36-38% concentration.

Step 8. the finalstep in the process, involves ame -r34 a reduction 'of "the carbonyl-group of thecompound produced Step '7 to a -hydrox yl g'roup.

This "reduction can be efiected in good yields by using either of two methods.

one method involves the use of sodium *borohydride, Na'I-LzB. Itis=preferred to'carryout the reductionusing N'aHlB inthea' presence of L analcohol such as, for instance, etli'ano'lormethanol. This method yields "amixture of (IZZY-three "and (dD-erythro forms of the fiiiofosul fonylphenylamidopropanediolsof the invention.

The alternative method of Step S i-s referred to as the;MeerweimPonndorf verly-reduction. This reduction 'methodis described by A. 'L; 'Wilds on age 203 of Chapter 5 of Organic Reactions, volume '2; John wiley' 'zlz'sons, The, N. Y. (1944) This method" of-ieduction givesmainly (dlfithre'o form of the fluorsulfonylphenylamidopropanediols. v

The individual thre'o sti eoisomeric form of the fl'uorosulfonylphenylainidopropanediols -can beresolved intotheiroptical'isomers'foHowing the completion of Step 8 and hydrolysis witha'hydrohalide acid to the amine salt. This resolution can'be carried out by forming-an acid salt of the racemic'ami'ne oftli'reo forinwi-th an optically active acid such as, for'instane, (d) -camphor sulfonic acid, '(l)"'-=caniphor sulfonic acid, (d) -tartaricacid, :(l) -tartaric "acid, -(d)"-'-mand'elic acid and -(Z) -mandelic acid; by "treating the hydrolialide salt with one of'the'above-namecl acids inthe presence of an equivalent quantity of silver oxide or silver "carbonate; -separating the two diastereoisomeric products by recrystallization from a solvent such' 'as, for instance, a lower aliphatic alcohol or mixtures 'of the same with water or other organic solvents; "and then -re-' generating the" individual optically" active-isomers from the separated diastereoisomeri'c addition salts by treating each one separately with-caustic or with-a basic'ion exchange" resin.

When carrying out, the resolutionfassetforth above, it-is desirable butnotessentiarto choose the form of the optically active acid so that the diaster'eoisomer of which the" desired *optical 'isomer is *a part will separatefrom' the crystallizationsolution first.

The compounds" of the '-presentinvention are useful in the i preparation of 5 other organic compounds, such as for instance "the sulfona'midohenyiamido-i ,-3 -'pi'op ndiols of my copending application "Serial" No. 296,959, filed-concurrently herewith. "I'he compounds find further us as drugs in the control of bacteriar and rickettsial infections. 'They' are-also--of *iijsefin 'v'iral and fungal infectionsjand find 'particular use as anuba'ctefial agents and'in the control "of-the growth of microorganisms. v I

In order to more fully under'stand' the invention, reference "should be "had to the folldw'ing illustrative xa'mms Example 1 r t n 9 d 73 F 97 ffi -fll om ii 'phenyl} 2- (alpha,alpha dichlroacetamido 13- propanediol on gnu-docket 6 manganate; (Step-1a.") The mixture i'sh'eated to a temperature "of 50 C. During theheating period, the =niixture is stirred. -'At"the' end of 2 .5 hours, 163 g. of Epota'ssium -2perinang'anate is added and 'the'reaction is allowed 'to continue for a period of 325"hour's. The excess permangana'teis removed byadding slowly to the reaction mixture a saturated "solution of sodium sul- 'fite until the purplecolor of the mixture is discharged. The mixture ds-filtered with "the aid of diatomaceous *earth to insure--remo'va1 of manganese dioxide. The filter cake is collected and washed with acetone and benzene.

The washed product is'extracted'from'the aqueous acetone filtrate with benzene. The solvents removed from the extract containing the desired jpr'odlict by distillation at atmospheric "pressure. The product itself is 'fra'tionated through a packed'co'lurhn to"giVe'a94="g. yield. 263 g. of starting rnaterial is 'reesvere'd. 'The product is crystallized from SQO cc. of "Skellysolve C "1'10 give 91" g. of inat'rial' melting 7'178.5"C. The product, p fiuorosiilfonylactoplienone, has the formula Ln nOH.

To a stirred s0li'1tionf-o'f '2022 g. of' p' fiuor'osulfonylacetophenone inflq "fciof gla'c'ial acetic acid there is a'dded'slowly l59 g.-of l5romine. After the first 15 drops of bi oifiine afe added;a period of about 13 minutes elapses before the bromine is decolorized. The brominatidnis continued at such a rate "that the reaction temperature is maintained at or below 30 C. Crystals separate from the reaction mixture towards the end of the bromination. "The resulting ispoured into 3 l. of ice and water. The white crystals are filtered, collected and" dried. 'Theyi'eld'is '257 g. of product having a melting range "of from 103 to 108.5 C. 'This'cru'deproductis"crystallized from 400' cc.- or benzene to'fgive 188 g. of material, MJP. 108-110" C. "Afurther quantity'ofproduct can be obtained by recry's'tallizingthe residue obtained from the benzene filtrate. Th'eproduct of this reaction is p-fiuorosulfonylph'enacylbromide, whose formula is asfollows:

Anal. Calc'df for CsHGBi FOSfCf351.18; H, 2.15; Br, 2a.43. Found: "34.30 n, 2127; m, 28.32.

:A suspension or ieo gz r -p'-fludrosdlfonyl13henacyl bromide in 1 liter ofan'isole'is stirredat normal room temperature as g. of powdered hexamethylenetetramine isadded. jThe mixture is stirred for a' peridd of one hour during which time the temperature of the reaction mixture risesto 38 C. "Theresultingslurr'yfispoured into stirred ice water'whieh"contains300 g. of sulfur dioxide dissolved' in a. us desired prodiicts'epa'rates as a'whitep'o'wder. It is filtered, collected, 'was hedfwita'ethanol" and "dried. The yield of p hydroxyinethylariiino) acetyllben 'zenes'ulfonylifludride 'sul'fite"-is 186' g. A further 61 g. of'profduct' isobtainedjfrom'the aqueous layer of the filtrate by' allowingit to evaporate. The formula of this product is r I To a stirred suspension-of 245 g, ar s-unydroxyinethylafnino) aotyll'benzene'siilfonyl fluo- 'ride sulfite in 200 cc. of concentrated hydrochloric acid there is added 400 cc. of absolute ethanol. The reaction mixture is refluxed for a period of one hour. During this period most of the solid dissolves. On cooling the mixture crystals separate. These are filtered, collected, and washed with absolute ethanol. The filtrate is concentratedto give more product. The yield of product in the form of light tan needles is 136 g. The product, p (aminoacetyl)benzenesulfonyl fluoride hydrochloride, has the formula:

A suspension of 136 g. of p-(aminoacetyDbenzenesulfonyl fluoride, hydrochloride, in 350 cc. of dichloroacetyl chloride is maintained at refiux temperature for a period of one hour. The solid dissolves with evolution of hydrogen chloride gas. The resulting solution is cooled in an ice bath. A solid impurity separates and is removed from the system. The desired product, p- (alpha,alpha dichloroacetamido) acetyllbenzenesulfonyl fluoride, is obtained from the filtrate by concentrating and diluting with benzene and Skellysolve C.

The yield of the crude fluoride is '71 g. This is crystallized from benzene to give 57 g. of tan needles melting at 136 C. and solidifying with melting taking place at 148.5-150 C. The product has the following formula:

Anal. Calcd. for C1oHsC12FNO4S: C, 36.60; H, 2.46; Cl, 21.61. Found: C. 36.89; H, 2.74; Cl, 21.72.

A suspension of 3.28 g. of p-[(alpha,alpha-dichloroacetamido)acetyllbenzenesulionyl fluoride in 12 cc. of 95% ethanol containing 0.2 g. of sodium bicarbonate and 3.5 cc. of 36-3'l% aqueous formaldehyde is stirred at a temperature of 35 C. for a period of 30 minutes. External heating is discontinued. Stirring is continued for an additional two hours. The solution is then diluted with 250 cc. of ice and water. The introduction of water drives out a gum which crystallizes on standing. The yield of crystalline product is 2.43 g., M. P. l1'l-122 C. This is crystallized from 14 cc. of ethylene dichloride to give 1.30 g., M. P. l33-134 C. The product, p- [alplia- (alpha,al pha dichloroacetamido) beta hydroxypropionyl]benzenesulfonyl fluoride, has the structural formula F-E-Q- -d -crcoH Anal. Calcd. for CnHmClzFNOsS! C, 36.88; H, 2.81. Found: C, 36.95; H, 3.16.

A solution of 1 g. of plalpha- (alpha,al pha dichloroacetamido) beta hydroxyprop'ionyllbenzenesulfonyl fluoride in 25 cc. Of warm isopropyl alcohol is added to a solution of l g. of aluminum isopropoxide in 35 cc. of isopropyl alcohol. The mixture is refluxed beneath a packed distilling column as distillate is taken from the top of the column over a period of one and one-half hours. The residue, yellowish in color, is further concentrated under reduced pressure until about 20 cc. remains. The yellow gum is diluted with 45 cc. of hydrochloric acid and cooled in ice. The gum is extracted from the acid solution with ethyl acetate, dried and concentrated under reduced pressure. The residue is dissolved in ethylene dichloride. Carbon tetrachloride is added to the ethyl dichloride ex tract until a precipitate appears. The crystals, which separate on standing, are (111) -threo- 1-(p fiuorosulfonyl)-2-(alpha,alpha dichloroacetamido)-l,3-propanediol. The yield is 0.46 g. melting 159-163 C. A 0.42 g. portion crystallized from 30 cc. ethylene dichloride gave white prisms melting 167-168" C.

Anal. Calcd. for C1iH12C12FNO5SZ Found: S, 8.82.

(d1) -Threo-1- (p fluorosulfonyl) -2-(alpha,alpha dichloroacetamido) 1,3 propanediol has given evidence of great value as an antibacterial agent against such microorganisms as Salmonella typhimurium, streptococcus agalactz'ae, and Staphylococcus aureus.

Example 2 Preparation of (d) -threo-1-(p-fluorosulfonyl) 2 (alpha,a1pha dichloroacetamido) 1,3 propanediol OH NHCOCHCh (d)threo form The intermediate compound in this synthesis, the monosuccinyl derivative of (d1) -threo-1-(pfiuorosulfonylphenyl) -2-(alpha,alpha dichloroacetamido)-1,3-propanediol, is prepared according to the following procedure:

A mixture of 36 g. of (all) -threo-1-(p-fiuorosulfonylphenyl) 2 (alpha,alpha dichloroacetamido) -1,3propanediol and 10 g. of succinic anhydride is finely pulverized and heated to a temperature of C. while being stirred. The mixture is heated for a period of five hours. It is then cooled. The residue is suspended in water. Sodium bicarbonate is added to the aqueous suspension until the pl-I is 7.5.

The resulting solution is filtered to free it of any insoluble residue. The solution is made acid with dilute hydrochloric acid. During the acidification, the solution is stirred and surrounded by an ice bath. The desired monosuccinyl compound crystallizes from the solution.

To a'stirred-solution of 4.6 g. of the acid monosuccinyl derivative, of (all)-threo-1-(p-fluorosul-- fonylphenyl) 2- (alpha,alpha dichloroacetamido)-1,3-propanediolin 30 cc. of acetone, there is added slowly asolution of, 3.34 g. of strychnine in20 cc. of chloroform. The salt is obtained by concentrating ;the;solution. The salt is fractionallycrystallized from amixture of chloroform and acetone to give the (ll-strychnine salt of the monosuccinyl derivative of (D-threo-l- (p fiuorosulfonylphenyl) 2 (alpha,alphadi chloroacetamido) -1,3 propanediol and the (l)- strychnine salt of the monosuccinyl derivative of (ell-three l (p-fiuorosulfonylphenyl)-2- (alpha,alpha dichloroacetamido)-l,3-propanediol.

The (ll-strychnine salt of the. monosuccinyl derivative of (d) threo-l-(p-fiuorosulfonylphenyl) 2 (alpha,alpha-dichloroacetamido) 1,3-propanediol is dissolved in a small amount of water and made acid to Congo red paper with dilute sulfuric acid. The monosuccinyl derivative of (d) -threo-1- (p-fluorosulfonylphenyl) -2- (alpha,alpha-dichloroacetamido 1,3 propanediol separates as crystals. The crystalline material is converted to (d)-threo-l-(pfiuorosulfonylphenyl) 2 (alpha,alpha dichioroaceta- 9 mido-L3-propanedio1; by, warming. in 0.1 7151i 15- drochloric acid.

Example 3' Preparation, of (Z).-threo-1-(p-iiuorosulfonylphenyl) 2- (alphaalpha;dichlorpacgzamido 1,3- propanediol on uric-0929, 9

(l)-threo form The (l)-strychnine salt of the monosuccinyl derivative of (l)-threo-1-(p fluorosulfonylphenyl) 2 (alpha,alpha-dichloroacetamido)- 1,3-propanedio1 (prepared in Example 2) is dissolved in water and made acid to Congo red paper with dilute sulfuric acid. The monosuccinyl derivative of (Z) -threo-1-(p-fiuorosulfonylphenyl) 2 (alpha,alpha-dichloroacetamido)- 1,3-propanedio1 separates from the solution. This is converted to (Z) -threo-1-(p-fiuorosulfonylphenyl) 2 (alpha,alpha-dichloroacetamido)-1,3-propanediol by warming with 0.1 N hydrochloric acid.

I claim:

1. A compound of the formula,

where R is a member of the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy radicals, with potassium permanganate and magnesium nitrate, whereby a compound of the foris obtained; (2) adding to a solution of the latter compound a halogenating agent, whereby a phenacyl halide of the formula is produced, where X is a member of the class consisting of chloro, bromo and iodo radicals;

(a1 m xin the, mama ha de unassi n with hexamethylenetetramine; in afliguid, medium; (4) effecting conversion of the resulting hexamethylenetetraminium lialide to a benzenesulfonyl fluoii'd'esulfite of, the iorrnula using sulfur dioxide and water; (5) hydrolyzing the sulfite with a mineral acid to obtain a salt of the amine of the forgi ula (6) N-acylating the latter compound with an acyl halide in the absence of an acid acceptor to pro duce a compound of the formula where acyl is a member of the class consisting of acetyl, chloroacetyl, bromoacetyl, dichloroacetyl and dibromoacetyl radicals; (7) mixing the latter compound in the presence of a weak inorganic base with formaldehyde, whereby a compound of the formula is obtained; (8) effecting chemical reaction between the latter compound and a member of the group consisting of aluminum isopropoxide and sodium borohydride and recovering a compound of the formula 6. In a process for obtaining (dZ)-threo-1-(p fluorosulfonylphenyl) -2-(alpha,alpha dichloroacetamido)-1,3-propanediol, the steps comprising mixing p-ethylbenzenesulfonyl fluoride with magnesium nitrate and potassium permanganate, recovering p-fluorosulfonylacetophenone thus formed, brominating the latter compound with bromine in the presence of glacial acetic acid to obtain p-fluorosulfonylphenacyl bromide, mixing the latter compound with hexamethylenetetramine and subsequently with sulfur dioxide and water to obtain p [(hydroxymethylamino)- acetyllbenzenesulfonyl fluoride sulfite, hydrolyzing the latter compound so obtained with hydrochloric acid, recovering the p-(aminoacetyD- benzenesulfonyl fluoride, hydrochloride, N-acylate ing the latter compound with dichloroacetyl chloride to obtain p-[(alpha,alpha dichloroacetamido)-acetyl]benzenesulfony1 fluoride, mixing the latter compound so obtained with aqueous formaldehyde in a dilute alkaline solution, recovering p-[alpha- (alpha,alpha dichloroacetamido) beta hydroxypropionyl]benzenesulfonyl fluoride, reducing the latter compound with aluminum isopropoxide in the presence of isopropyl alcohol, and recovering (dl)-threo-1-(-pfluorosulfonylphenyl) -2-(alpha,alpha dichloroacetamido) -1,3-propanediol.

11 12 '7. In a, process for the preparation of a. comwith formaldehyde in the presence of a weak inpound of the formula organic base, whereby hydroxymethylation occurs to give a, compound. of the formula B N R 0 E flfikcy] I 5 0 o NH-Acyl 2 H CHOH F-(S) -en-omon where R is a member of the class consisting of hydrogen, halogen, lower alkyl and lower alkoxy Re ere s C d in e fi Of s P e radicals the step comprising mixing a compound 10 Long a1 Am Chem, 300.," vol. 71, July of the formula 1949, pp. 2473-5. 

1. A COMPOUND OF THE FORMULA, 